Cerebrotendinous xanthomatosis: An inborn error in bile acid synthesis with defined mutations but still a challenge

Cerebrotendinous xanthomatosis [CTX] is a rare disease characterized by the accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene [CYP27A1] involved in bile acid synthesis. Disruption of this gene in mice does not give rise to xanthomas. The gene defect leads to reduced bile acid synthesis with a compensatory increase in the activity of the rate-limiting enzyme in bile acid synthesis, cholesterol 7 alpha-hydroxylase. This leads to a marked accumulation of 7 alpha-hydroxylated bile acid precursors, in particular 7 alpha-hydroxy-4-cholesten-3-one. The latter oxysterol passes the blood-brain barrier and is an efficient precursor to cholestanol. The activity of cholesterol 7 alpha-hydroxylase is normalized by treatment with bile acids. Such treatment reduces the xanthomas in CTX patients in parallel with decreased cholestanol levels. The relationship between the accumulation of cholestanol and the development of cholesterol-rich xanthomas has however not been clarified and a suitable animal model is still lacking. (C) 2010 Elsevier Inc. All rights reserved.